Cancers which originate in the lymphatic system that comprises the bone marrow, spleen, thymus and lymph nodes are commonly termed “lymphomas” and account for about half of the blood cancers that occur each year.
A type of lymphoma is multiple myeloma which is characterized by the uncontrolled proliferation of malignant plasma cells in the bone marrow and production of monoclonal immunoglobulin detectable in serum and/or urine. Latest reports demonstrate early age of onset and increase in incidence, though the peak age of occurrence of multiple myeloma is 65 to 70 years of age. According to latest statistics, 1 to 5 per 100,000 individuals is afflicted each year worldwide with a greater incidence in the West. Men are more susceptible to myeloma and the overall incidence range varies from ˜0.5-1/100,000 among Asians to as high as ˜10-12/100,000 among African-American men. It is the second most prevalent hematologic malignancy in the United States, and it is estimated that ˜20,580 men and women (11,680 men and 8,900 women) was diagnosed with and ˜10,580 men and women died of myeloma in 2009 (NCI, NIH). The most common manifestation of the disease is bone destruction due to increased osteoclastic bone resorption and decreased bone formation. The median overall survival for myeloma patients is 4 to 5 years, ranging from <6 months to >10 years according to distinct prognostic factors.
Currently, the two most efficacious treatment options for patients with multiple myeloma are tandem high-dose chemotherapy, followed by autologous stem cell infusion, or allogeneic hematopoietic stem cell transplantation after myeloablative therapy. A choice among different chemotherapeutic drug combinations happens to be the first-line therapy in patients with refractory or relapsed disease or who might face complications with autologous stem cell transplantation. Commonly used agents either alone or in combination include Dexamethasone, Vincristine, Doxorubicin, Melphalan, Cyclophosphamide, Etoposide, and Cisplatin. New agents such as the immunomodulatory drugs Thalidomide and Lenalidomide, and the proteasome inhibitor Bortezomib, have been introduced for the treatment of relapsed multiple myeloma and have shown to induce significant recovery in patients. Moreover, the efficacy of chemotherapeutic drugs combined with stem cell transplantation did not meet expectations due to high levels of toxicity. Nevertheless, complete cure is very rarely achieved due to persistence of residual disease. Therefore, there is an urgent need for the development of promising new therapeutic candidates.
Another type of lymphoma is thymoma that arises from the thymus gland, usually with an indolent growth pattern; however, local invasion and/or metastases may occur. This tumor is associated with unique paraneoplastic syndromes (myasthenia gravis, pure red cell aplasia, hypogammaglobulinemia and other autoimmune diseases). The overall incidence of thymoma is rare; with 0.15 cases per 100,000 and account for only 0.2% to 1.5% of all the malignancies. Thymomas have been found to occur at all ages, from patients of 8 months to 90 years with a mean age of about 53 years and have equal gender distribution. Locally advanced thymoma requires a multimodality treatment approach with a combination of surgery, chemotherapy and radiation therapy to reduce the chances of recurrence and improve survival. The common chemotherapeutic drugs used for the treatment of thymoma include: cyclophosphamide, doxorubicin, etoposide, cisplatin and paclitaxel. Hormonal therapy is also occasionally applied that involves corticosteroids.
The limitations of using multiple and high dose of chemotherapeutic drugs are elevated levels of toxicity which leads to harmful side-effects. Moreover, relapse is also common due to resistance to these drugs.
In the last decade, cancer immunotherapy has emerged as the new therapeutic option for multiple myeloma patients otherwise unresponsive to traditional modes of cancer therapy or as combination therapy to reduce the harmful effects of other cancer treatments. Tumor immunotherapy based approach stimulates the innate and adaptive cells of the host immune system for efficient induction and maintenance of endogenous anti-tumor immune responses necessary to recognize and eradicate malignant tissue. Moreover, immunosuppressive cells such as regulatory T cells or myeloid suppressor cells produced by the myeloma needs to be eliminated for success of cancer immunotherapy.
Different bacteria belonging to the Mycobacterium family display remarkable adjuvant properties and modulate the host immune response. Heat-killed saprophytic mycobacteria such as Mycobacterium vaccae and related members have been found to be effective and are being currently exploited in ongoing clinical trials. Another mycobacterium that has been widely used as adjunct to multi-drug therapy in leprosy is Mycobacterium w, currently known as MIP. Unlike BCG, MIP retains its immunologic potential even after it is killed. Both in vitro and in viva studies have shown that killed MIP enhances immune responses to Mycobacterium leprae antigens. Recent studies have shown that MIP is effective in the therapy of other chronic diseases such as tuberculosis, HIV infection, cancer, psoriasis and bronchial asthma.
To date, myeloma remains a lethal disease even though huge progress has been made in understanding its pathophysiology and biology and advent of new aggressive chemotherapeutic drugs. Unfortunately, myeloma largely remains incurable with a history of relapse in majority of patients and complete remissions are still rare. Similarly, thymoma also has a high incidence of recurrence with increased risk of having another type of cancer and metastasis to other organs. Hence, lifelong follow-up after surgical removal of thymoma is necessary. Moreover, the toxicity of anticancer agents such as Cyclophosphamide, one of the most common drugs used in the treatment of various cancers, continues to pose a problem for the use of these chemotherapeutic agents. In addition, extrapolation of in vitro studies to treatment regimens for cancer patients has its share of inherent difficulties. Accordingly, it would be beneficial to develop new approaches that can selectively prevent the toxic side effects of Cyclophosphamide such as bladder and cardiac toxicity and hair loss and at the same time has the potential to maintain or enhance its therapeutic efficacy.